Impact of imperatorin and isoimperatorin on the pharmacokinetics of abemaciclib both in vivo and in vitro

<title>Abstract</title> Abemaciclib is used for the treatment of breast cancer (BC) in clinics. The combination of abemaciclib and imperatorin or isoimperatorin has been studied <italic>in vitro</italic> and <italic>in vivo</italic> to explore the pharmacokinetics of Chinese herbs and anti-cancer medicines. Eighteen male SD rats were randomly allocated to three groups: control, isoimperatorin (50 mg/kg) and imperatorin (50 mg/kg). The concentration level of abemaciclib in the plasma was determined using the UPLC-MS/MS technique on rats. Molecular simulation docking with AutoDock 4.2 software and rat liver microsome incubation were utilized to analyze the inhibitory mechanisms. In this study, we found that co-administration of imperatorin and isoimperatorin resulted in higher AUC _(0−∞) and C _max values and lower CLz/F values (p &lt; 0.05). In addition, both imperatorin and isoimperatorion showed moderate inhibition for abemaciclib with IC ₅₀ values of 6.79 µM and 6.56 µM, respectively. Intriguingly, we found that imperatorin, isoimperatorin and abemaciclib exhibit similar binding capacities with CYP3A4. Moreover, the results indicated that imperatorin and isoimperatorin significantly impaired the pharmacokinetics of abemaciclib <italic>in vivo</italic> . Therefore, our research suggests that the combination of abemaciclib and imperatorin or isoimperatorin should be considered more in clinical practice.